Immunologic protection, the essence of any effective vaccine, is generally obtained by exposure to an agent that simulates disease experience immunologically. In the case of infection with the AIDS virus, it is not clear that disease experience itself results in effective immunity that could confer protection. Through one immunologic parameter of specific immunity, the presence of neutralizing antibody, may correlate with a more favorable short term clinical course in some risk groups, overall, the immunologic prerequisites for protection against AIDS remain unknown. The goal of any potential AIDs vaccine must, therefore, be to induce the strongest possible T cell and B cell immunity in an individual prior to exposure to the AIDS virus or infected cells. Experience from murine and feline retroviruses suggests that immunity to the envelope proteins may be most important for protection. However, the AIDs virus gp120 envelope protein shows substantial variability in the distinct isolates sequenced to date. Consequently a generally effective enveloped-directed vaccine will need to incorporate the important B cell and T cell epitopes from all isolates in the form of highly immunogenic proteins or peptides. This project will systematically analyze peptides representing important T cell sites in gp120 and use the insights gained, to develop highly immunogenic peptide component vaccine constructs for AIDS. The initial site to be intensively studied will be the env T1 site that my collaborators and I recently reported. Each site will be examined in four phases. In Phase 1 studies, the limits of the site will be carefully determined and the minimal peptide with full immunologic activity identified. In Phase 2 studies, the stringency of recognition of the site will be examined by systematically identifying and characterizing critical residues. Cross-recognition of the site as it exists in all sequenced isolates of the AIDs virus worldwide will be carefully characterized as will important practical substitutions that simplify handling and facilitate use as a component in a vaccine construct. In phase 3, the potentially important antibody response to these T-cell sites will be examined in detail. Finally, in Phase 4, the structure-activity insights from Phases 1-3 will be used to select peptide components to be used, along with B cell sites characterized by others, in developing peptide component vaccine constructs. Through repeated design, synthesis and testing, constructs will be engineered with the desired immunologic activity. The optimized peptide component vaccine constructs that emerge should reveal important principles for engineering synthetic or recombinant vaccines against AIDS and will themselves be candidates for continuing preclinical studies.